Two classes of neuropeptides, somatostatin and the endogenous opioids, have been highly conserved during evolution, are expressed in early stages of embryogenesis, and function through similar families of G-protein coupled receptors. To investigate their roles in development and in adult function, we are systematically mutating the genes for somatostatin and its five receptors, and for the three endogenous opioid encoding genes. We have introduced a null allele at the loci for somatostatin, the somatostatin receptors 3 and 4, proopiomelanocortin, and dynorphin, respectively. The POMC null mutant shows obesity, adrenal insufficiency, and altered pigmentation, thus modeling this genetic form of human obesity. The SST null mutant shows a pleiotropic phenotype, with defects from motor learning to steroid regulation. Phenotypic alterations in the SSTR 3 and 4 null mutants and in the dynorphin null mutant are not apparent under normal conditions; mutants are undergoing a systematic scan for phenotypes.